Free-energy calculations of residue mutations in a tripeptide using various methods to overcome inefficient sampling

Previous free-energy calculations have shown that the seemingly simple transformation of the tripeptide KXK to KGK in water holds some unobvious challenges concerning the convergence of the forward and backward thermodynamic integration processes (i.e., hysteresis). In the current study, the central residue X was either alanine, serine, glutamic acid, lysine, phenylalanine, or tyrosine. Interestingly, the transformation from alanine to glycine yielded the highest hysteresis in relation to the extent of the chemical change of the side chain. The reason for that could be attributed to poor sampling of φ2 /ψ2 dihedral angles along the transformation. Altering the nature of alanine's Cβ atom drastically improved the sampling and at the same time led to the identification of high energy barriers as cause for it. Consequently, simple strategies to overcome these barriers are to increase simulation time (computationally expensive) or to use enhanced sampling techniques such as Hamiltonian replica exchange molecular dynamics and one-step perturbation. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.